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Donor-recipient mismatch for common gene deletion polymorphisms in graft-versus-host disease

Abstract

Transplantation and pregnancy, in which two diploid genomes reside in one body, can each lead to diseases in which immune cells from one individual target antigens encoded in the other's genome. One such disease, graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT, or bone marrow transplant), is common even after transplants between HLA-identical siblings, indicating that cryptic histocompatibility loci exist outside the HLA locus. The immune system of an individual whose genome is homozygous for a gene deletion could recognize epitopes encoded by that gene as alloantigens. Analyzing common gene deletions in three HSCT cohorts (1,345 HLA-identical sibling donor-recipient pairs), we found that risk of acute GVHD was greater (odds ratio (OR) = 2.5; 95% confidence interval (CI) 1.4–4.6) when donor and recipient were mismatched for homozygous deletion of UGT2B17, a gene expressed in GVHD-affected tissues and giving rise to multiple histocompatibility antigens. Human genome structural variation merits investigation as a potential mechanism in diseases of alloimmunity.

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Figure 1: Association analysis of donor-recipient mismatch for common gene deletions in GVHD.
Figure 2: Cumulative incidence of acute GVHD during the first 100 days after HSCT (cohort C).
Figure 3: Multiple histocompatibility antigens derived from UGT2B17.

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References

  1. Gale, R.P. & Champlin, R.E. How does bone-marrow transplantation cure leukaemia? Lancet 2, 28–30 (1984).

    Article  CAS  PubMed  Google Scholar 

  2. Gale, R.P. et al. Identical-twin bone marrow transplants for leukemia. Ann. Intern. Med. 120, 646–652 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Randolph, S.S., Gooley, T.A., Warren, E.H., Appelbaum, F.R. & Riddell, S.R. Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants. Blood 103, 347–352 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Wang, W. et al. Human H-Y: a male-specific histocompatibility antigen derived from the SMCY protein. Science 269, 1588–1590 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Meadows, L. et al. The HLA-A*0201-restricted H-Y antigen contains a posttranslationally modified cysteine that significantly affects T cell recognition. Immunity 6, 273–281 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Warren, E.H. et al. The human UTY gene encodes a novel HLA-B8-restricted H-Y antigen. J. Immunol. 164, 2807–2814 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Vogt, M.H. et al. The DBY gene codes for an HLA-DQ5-restricted human male-specific minor histocompatibility antigen involved in graft-versus-host disease. Blood 99, 3027–3032 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Spierings, E. et al. Identification of HLA class II-restricted H-Y-specific T-helper epitope evoking CD4+ T-helper cells in H-Y-mismatched transplantation. Lancet 362, 610–615 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Ivanov, R. et al. Identification of a 40S ribosomal protein S4-derived H-Y epitope able to elicit a lymphoblast-specific cytotoxic T lymphocyte response. Clin. Cancer Res. 11, 1694–1703 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Skaletsky, H. et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 423, 825–837 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Iafrate, A.J. et al. Detection of large-scale variation in the human genome. Nat. Genet. 36, 949–951 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. McCarroll, S.A. et al. Common deletion polymorphisms in the human genome. Nat. Genet. 38, 86–92 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Conrad, D.F., Andrews, T.D., Carter, N.P., Hurles, M.E. & Pritchard, J.K. A high-resolution survey of deletion polymorphism in the human genome. Nat. Genet. 38, 75–81 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Colin, Y. et al. Genetic basis of the RhD-positive and RhD-negative blood group polymorphism as determined by Southern analysis. Blood 78, 2747–2752 (1991).

    CAS  PubMed  Google Scholar 

  16. Murata, M., Warren, E.H. & Riddell, S.R. A human minor histocompatibility antigen resulting from differential expression due to a gene deletion. J. Exp. Med. 197, 1279–1289 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. McCarroll, S.A. et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat. Genet. 40, 1166–1174 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Schulze, J.J. et al. Doping test results dependent on genotype of uridine diphospho-glucuronosyl transferase 2B17, the major enzyme for testosterone glucuronidation. J. Clin. Endocrinol. Metab. 93, 2500–2506 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Terakura, S. et al. A UGT2B17-positive donor is a risk factor for higher transplant-related mortality and lower survival after bone marrow transplantation. Br. J. Haematol. 129, 221–228 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Yang, T.L. et al. Genome-wide copy-number-variation study identified a susceptibility gene, UGT2B17, for osteoporosis. Am. J. Hum. Genet. 83, 663–674 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Terakura, S. et al. A single minor histocompatibility antigen encoded by UGT2B17 and presented by human leukocyte antigen-A*2902 and -B*4403. Transplantation 83, 1242–1248 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Kamei, M. et al. HapMap scanning of novel human minor histocompatibility antigens. Blood 113, 5041–5048 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Miklos, D.B. et al. Antibody response to DBY minor histocompatibility antigen is induced after allogeneic stem cell transplantation and in healthy female donors. Blood 103, 353–359 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Miklos, D.B. et al. Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission. Blood 105, 2973–2978 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Zorn, E. et al. Minor histocompatibility antigen DBY elicits a coordinated B and T cell response after allogeneic stem cell transplantation. J. Exp. Med. 199, 1133–1142 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Cutler, C. et al. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood 108, 756–762 (2006).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Xue, Y. et al. Adaptive evolution of UGT2B17 copy-number variation. Am. J. Hum. Genet. 83, 337–346 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Petersdorf, E.W., Malkki, M., Gooley, T.A., Martin, P.J. & Guo, Z. MHC haplotype matching for unrelated hematopoietic cell transplantation. PLoS Med. 4, e8 (2007).

    Article  PubMed Central  PubMed  Google Scholar 

  29. Martin, P.J. et al. Increasingly frequent diagnosis of acute gastrointestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol. Blood Marrow Transplant. 10, 320–327 (2004).

    Article  PubMed  Google Scholar 

  30. Nichols, W.C. et al. Polymorphism of adhesion molecule CD31 is not a significant risk factor for graft-versus-host disease. Blood 88, 4429–4434 (1996).

    CAS  PubMed  Google Scholar 

  31. International HapMap Consortium . A haplotype map of the human genome. Nature 327, 1299–1320 (2005).

    Article  Google Scholar 

  32. Korn, J.M. et al. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat. Genet. 40, 1253–1260 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to thank the patients, donors and clinical care teams at Helsinki University Central Hospital, the Dana-Farber Cancer Institute and the Fred Hutchinson Cancer Research Center. We also wish to thank D. Sese and colleagues at the Brigham and Women's Hospital Tissue Typing Laboratory; the Ted and Eileen Pasquarello Tissue Bank; Q. Yang and colleagues at the Quality Assurance Office for Clinical Trials at Dana-Farber Cancer Institute; E. Lander, Y. Ofran, J. Chien and M. Daly for helpful conversations on the project and data; and B. Blazar, C. Keever-Taylor and D. Senitzer for providing patient samples for the Nichols et al. cohort further studied here. This work was supported by the Broad Institute of MIT and Harvard (D.A., S.A.M.), the Academy of Finland (L.V., H.T., J.P.), the Helsinki University Central Hospital Research Fund (L.V.), the Fred Hutchinson Cancer Research Center, a Lilly Life Sciences Research fellowship (S.A.M.), the S. Juselius Foundation (J.P.), the Center of Excellence Program of the Finnish Academy (A.P.) and the National Institutes of Health (HA070149 to J.H.A.; AI29530 to J.R.; AI33484, CA18029 and HL087690 to J.A.H.).

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Authors

Contributions

S.A.M., J.E.B. and D.A. developed an initial study plan and refined this plan with insights from R.J.S., J.R., A.P., E.H.W. and P.J.M. Patient collections including DNA samples were established and/or further developed by L.V., H.T., T.R. and J.P. in Helsinki; J.E.B., S.J.L., J.H.A., J.R. and R.J.S. in Boston; D.G. in Michigan; and P.J.M., S.J.L., B.S. and J.A.H. in Seattle. Analyses of patient clinical data were led, performed and/or further analyzed by L.V. and T.R. at Helsinki University Central Hospital; S.J.L., J.E.B., J.H.A., R.J.S. and J.R. at Dana-Farber Cancer Institute; and B.S., P.J.M., S.J.L., E.H.W. and J.A.H. at the Fred Hutchinson Cancer Research Center (FHCRC). Deletion polymorphisms were genotyped by S.A.M., H.T. and S.D.C., using molecular assays developed by S.A.M. B.Z. and L.P.Z. analyzed array-based data to genotype deletions and analyzed association and time course in the FHCRC cohort. S.A.M. performed statistical analyses of genotype-phenotype correlation with feedback from other authors, especially P.J.M., A.P. and D.A. S.D.C. and H.T. performed ELISA experiments. S.A.M. wrote the manuscript with extensive input and feedback from coauthors.

Corresponding author

Correspondence to Steven A McCarroll.

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McCarroll, S., Bradner, J., Turpeinen, H. et al. Donor-recipient mismatch for common gene deletion polymorphisms in graft-versus-host disease. Nat Genet 41, 1341–1344 (2009). https://doi.org/10.1038/ng.490

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